Patent GB-875533-A (GB)
Title: Improvements in and relating to 5-alkylsulfonyl-2-alkoxyanilines and their salts
IPC: C07C311/37
Filed: 1957-10-16
Abstract: The invention comprises compounds of the formula <FORM:0875533/IV (b)/1> and acid addition salts thereof with non-toxic anions, wherein R1 is an alkyl group having 3 or 4 carbon atoms and R2 is an alkyl or haloalkyl group of 1 to 5 carbon atoms.  When R2 is a haloalkyl group, specified groups include chloromethyl, trichloromethyl and fluoromethyl groups.  The compounds are prepared by reducing the corresponding nitro compound obtained by (1) nitrating a p-alkyl sulphonylphenyl alkyl ether produced by (a) oxidation of a p-alkyl mercaptophenyl alkyl ether, (b) alkylating an alkali metal p-alkoxy-benzene sulphinate produced by halosulphonating a phenyl alkyl ether and reducing the resulting sulphonyl halide, (c) alkylating a p-alkyl sulphonylphenol, produced by diazotising p-alkyl sulphonylaniline and decomposing, or by oxidising p-alkyl sulphonyl acetophenone, p-acetoxyphenyl alkyl sulphide or p-alkyl mercaptophenol, or (d) reducing p-halobenzenesulphonyl halide to the alkali metal sulphinate and alkylating and alkoxylating; (2) alkoxylating a 5-alkyl sulphonyl-2-halonitrobenzene produced by (a) reducing a p-halobenzenesulphonyl halide to the sulphinic acid alkali metal salt, alkylating and nitrating, (b) alkylating a p-halo-thiophenol, oxidising the resulting p-alkyl mercaptohalobenzene to the corresponding p-alkyl sulphonylhalobenzene and nitrating, (c) halosulphonating o-halonitrobenzene to a 4-halo-3-nitro-benzene-sulphonyl halide, reducing to the sulphinic acid alkali-metal salt and alkylating or (d) treating an alkali-metal 4-halo-3-nitro-benzene-sulphonate with a phosphorus pentahalide reducing the resulting sulphonyl halide and alkylating the sulphinic acid salt obtained; or (3) alkylating the 4-alkoxy-3-nitrobenzenesulphinic acid alkali-metal salt formed by alkoxylating a 4-halo-3-nitrobenzenesulphinic acid alkali-metal salt made according to 2(c) or 2(d) above. Alternatively the compounds may be made from salicylamide by alkylating, halosulphonating, reducing to the sulphinic acid salt, alkylating and converting the amide group to an amino group by the Hofmann degradation.  Compounds wherein R2 is a haloalkyl group are made by analogous methods.  The products may be converted into their acid addition salts such as the hydrohalides, sulphate, nitrate, perchlorate, benzene or p-toluene sulphonate, citrate, tartrate, phosphate or phthalate.  The compounds are used pharmaceutically as local anaesthetics (see Group VI).  In Examples (1) sodium p-methylsulphonyl phenolate is treated with 1-bromopropane, the resulting p - methylsulphonylphenyl propyl ether is nitrated 5-methylsulphonyl-2-propoxynitrobenzene and reduced to 5-methylsulphonyl-2-propoxyaniline which is converted to the hydrochloride; (2) and (3) p-methylsulphonylphenyl butyl ether, prepared as in (1), is nitrated to 5-methylsulphonyl-2-butoxynitrobenzene and reduced to 5-methylsulphonyl-2-butoxyaniline, either by hydrogen and Raney nickel or hydrazine and Raney nickel, and is converted to the hydrochloride; (4), (5) and (6) by the method of (1) there are prepared 4-ethylsulphonylphenyl propyl ether, 4-fluoromethylsulphonylphenyl isopropyl ether, 4 - chloromethylsulphonylphenyl butyl ether, the corresponding 2-nitro and 2-amino compounds and the hydrochloride, hydrobromide and hydroiodide respectively of the latter compounds; (7) p - chlorobenzenesulphonyl chloride is reduced with sodium sulphite, the resulting p-chlorobenzenesulphinic acid is treated with diethyl sulphate in aqueous sodium hydroxide to give p-ethylsulphonyl-chlorobenzene which is nitrated to 5-ethylsulphonyl-2-chloronitrobenzene, reduced to 5-ethylsulphonyl-2-chloro-aniline, alkylated with n-butanol and sodium to give 5-ethylsulphonyl-2-butoxy-aniline and converted to the sulphate; (8) p-chlorobenzenesulphinic acid is treated with n-propyl alcohol and sodium followed by bromoiodomethane to give p-bromomethylsulphonylphenyl propyl ether which is nitrated to 5-bromomethylsulphonyl-2-propoxynitrobenzene reduced to 5 - bromomethylsulphonyl-2-propoxyaniline and converted to the hydrogen tartrate; (9) 4-chloro-3-nitrobenzenesulphonyl chloride, formed by the action of chlorsulphonic acid on o-chloronitrobenzene, is reduced with sodium sulphite to 4 - chloro - 3 - nitrobenzenesulphonic acid, alkylated with 1-bromopropane to 5-propylsulphonyl - 2 - chloro - nitrobenzene, further alkylated with isopropyl alcohol to 2-isopropoxy-5-propylsulphonyl-nitrobenzene and reduced to 4-isopropoxy-5-propylsulphonyl aniline which is converted to the p-toluene sulphonate; (10) 4-chloro-3-nitrobenzenesulphinic acid is condensed with n-propyl alcohol and 2-fluoroiodoethane to give 5-(2-fluorethylsulphonyl)-2-propoxy-nitrobenzene which is reduced to 5 - (2 - fluorethylsulphonyl)-2-propoxy - aniline and (11) salicylamide is alkylated with 1-bromobutane to 2-butoxybenzamide which is chlorosulphonated to 2-butoxybenzamide-5-sulphonyl chloride, reduced with sodium sulphite to 2-butoxybenzamide-5-sulphinic acid condensed with 2-bromopropane to 2-butoxy - 5 - isopropylsulphonylbenzamide and treated with bromine and potassium hydroxide to give 2-butoxy-5-isopropylsulphonyl aniline which is converted to the dihydrogen phosphate.  Specification 544,849 is referred to.ALSO:Azo dyes are prepared by diazotizing 5-alkylsulphonyl- 2-alkoxy anilines of the formula:- <FORM:0875533/IV(c)/1> wherein R1 is an alkyl group of 3 or 4 carbon atoms and R2 is an alkyl or haloalkyl group of 1-5 carbon atoms and coupling with an appropriate component, for example, a phenol. In illustrations 5-methylsulphonyl- 2-propoxy-aniline is diazotized and coupled with (a) Laurent's acid, (b) Epsilon acid and (c) F salt giving on a wool/nylon mixture a rose, orange-red and lavender colour respectively.  Specification 544,849 is referred to.ALSO:Anaesthetic and fungicidal preparations comprise compounds of the formula <FORM:0875533/VI/1> or acid addition salts thereof, wherein R1 is an alkyl group of 3 or 4 carbon atoms and R2 is an alkyl or haloalkyl group of 1-5 carbon atoms (see Group IV (b)) and a carrier.  The anaesthetic preparations suitably take the form of sterile solutions for injection, ointments, lotions, liniments, sprays or dusting powders.  Sterile solutions suitably contain, in addition to the active ingredient, water or isotonic saline, a dispersing agent and one or more sympathomimetic or anti-bacterial agents such as beta phenylethylamine, tyramine, synephrine, phenylephrine, noradrenaline, epinephrine, phenyl propanolamine, ephedrine and "Paredrinol" (Registered Trade Mark). Anti-oxidant agents may also be present. Specified preparations comprise sterile solutions of 5-methylsulphonyl-2-propoxyaniline or 2-butoxy-5-ethylsulphonyl aniline in water or saline which may contain dispersing and anti-oxidant agents or another drug such as levarterenol bitartrate or, as a preservative, benzoic acid. Ointments may contain, for example, 0.1 to 2% of the anaesthetic constituent in a standard jelly, paste or salve base and also a fungicidal agent such as sodium propionate and/or, as antiseptic and antioxidant agents, alkyl parabens.  An emulsifying agent may also be present.  A spray composition may suitably contain 0.1 to 2% of the anaesthetic component together with surface active, anti-bacterial and anti-septic agents and a propellant.  The preparation of oily solutions and suppositories is also referred to.  A suitable fungicidal preparation for the treatment of plants comprises an aqueous composition containing 0.5% of 5-alkylsulphonyl-2-alkoxy aniline.  Specification 544,849 is referred to.